Neurodegenerative diseases pose an increasing challenge to public health as the population ages. Since only palliative treatments for these diseases are known, identifying preventable causes is of paramount importance. Work is in progress to evaluate the hypothesis that exposure to environmental neurotoxins increases the risk of developing neurodegenerative disease, particularly in genetically sus- ceptible individuals. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system; 1 of every 1000 deaths is due to this disease. The etiology of ALS is essentially unknown, but there is some evidence that environmental neurotoxins, particularly lead, may be involved. A case-control study to assess the role of these agents in ALS is underway. The primary hypothesis of the study is that cumulative lifetime exposure to lead is a risk factor for ALS; other neurotoxins of interest include mercury, solvents, and pesticides. The study will ultimately include 100 ALS cases, 50 clinical controls, and 200 population controls; presently 85 cases and 25 clinical controls are enrolled. Lead exposure is assessed by measuring bone lead using x-ray fluorescence, a newly developed technique capable of measuring noninvasively the low levels of bone lead present in the general population. Exposure to lead and other neurotoxins is also assessed using a structured in-person interview which investigates diet, life- style, and medical, residential, and occupational history. Dietary antioxidant intake will be evaluated as a protective factor and as a modifier of other exposure-disease relationships. Polymorphisms in genes involved in xenobiotic metabolism are also being studied, using PCR and RFLA, so that gene-environment interactions can be evaluated. Data will be analyzed using multivariate techniques including logistic regression, in order to examine the separate and joint effects of neurotoxins and other variables and to control for confounding. Insight gained from this study may contribute to measures for prevention or cure of this devastating disease. Moreover, elucidation of the role of the environment in ALS may provide a paradigm for future studies of other neurodegenerative diseases.